Solvent system for enhancing solubility

ABSTRACT

A pharmaceutically acceptable solution with a medicament suitable for filling a soft gelatin capsule is made from a solvent. The solvent contains a polymer, such as polyethylene glycol, and an acid salt of a compound having 3 or more carbon atoms, and a salt such as sodium propionate. The solvent may optionally contain a cosolvent, such as dimethyl isosorbide. The medicament may preferably comprise an analgesic such as aspirin or naproxen.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention relates to medicinal solutions suitable forencapsulation in soft gelatin capsules. More particularly, the inventionrelates to pharmaceutically acceptable solvent systems capable ofproducing a highly concentrated solution of a medicament, such asacetaminophen or naproxen, for use in a soft gelatin capsule.

[0003] 2. Description of Related Art

[0004] Soft gelatin capsules or “softgels” are, as their name implies,gelatin capsules that are softer than conventional caplets, capsules ortablets. They are commonly used to encapsulate liquids containing anactive ingredient or ingredients. Softgels are used to containconsumables, such as vitamins or pharmaceuticals, including products inthe over-the-counter market. Softgels are also used in many otherindustries, and have been used to encapsulate such diverse substances asindustrial adhesives and bath oils.

[0005] In the pharmaceutical industry, softgels provide many benefitsover conventional liquid and solid administration vehicles. Theydissolve in the stomach faster than compressed tablets. Tablets mustdissolve in the stomach or intestines and so generally retard the speedof onset of a medicament administered in a tablet form. Tablets are alsogenerally unsuited for administration of liquids. Hard gelatin orstarch-based capsules may be used for liquid or solid delivery systems.But, capsules are generally not appropriate for liquids because the hardgelatin or starch capsules may be either softened or entirely dissolvedby a liquid medicament. In addition, some air is usually trapped in ahard gelatin capsule, where a liquid “fill” is put into the capsule.This air bubble can affect the active ingredients and detract from theappearance of the product. Softgels are better than direct liquidadministration because liquids spill, and some medicaments may haveunacceptable or unpleasant taste even with taste masking agents.Softgels, on the other hand, dissolve rapidly in the stomach and thebody quickly absorbs the liquid interior of the softgel, so softgelsoffer an attractive means of administering a medicament.

[0006] Not all liquids may be enclosed in a softgel. Liquids containingmore than about 20% water by weight are generally not enclosed insoftgels, because the water tends to dissolve the gelatin shell.Propylene glycol, glycerin, low molecular weight alcohols, ketones,acids, amines, and esters all tend to degrade or dissolve the softgellayer gelatin to some extent. Thus, formulations that are enclosed in asoftgel cannot contain significant amounts of many well-known solvents.

[0007] Softgels are also somewhat sensitive to pH, and generally requirea pH in the encapsulated liquid from about 2.5 to about 7.5. Highlyacidic liquids may hydrolyze the gelatin, resulting in leaks, whilebasic liquids may tan the gelatin, resulting in decreased solubility ofthe gelatin shell.

[0008] Pharmaceutical liquids are usually enclosed in softgels as eitherviscous solutions or suspensions. Suspensions are pharmaceutically lessdesirable because they can settle during manufacture, which leads to aless uniform product. If a suspension is used, the solid particles in asuspension should be smaller than about 80 mesh, otherwise the softgelfilling equipment might not function optimally.

[0009] Suitable softgel solutions, however, can be difficult to achieve.The walls of a softgel are thicker than the walls of a caplet or a hardgelatin capsule. The softgel should be small enough for patientacceptance. The thickness of the walls reduces the available space forthe medicament. But, the softgel must contain sufficient quantities ofthe medicament to be effective. One approach, of course, is simply torequire the consumer to swallow more than one softgel to achieve anyadequate dose of the medicament. Consumers, however, prefer taking oneor two softgels, tablets or capsules and resist taking more than three.

[0010] The solution in the softgel must thus be highly concentrated.High concentration levels, though, strain the ability of conventionalsolvent systems to dissolve a sufficient quantity of the pharmaceuticalagent. A strong solvent, on the other hand, can degrade the gelatincoating. So, a frequent problem in softgel applications is dissolvingthe active ingredient or ingredients in a sufficiently small amount ofsolvent to provide a potent dose of the medicament in the softgel.Solvent systems must be used that are tailored to the specific needs ofa specific medicament or blend of medicaments. For example, U.S. Pat.No. 3,557,280 to Weber et al., issued January 1971, used a magnesiumsalt, polyvinylpyrrolidone and water to dissolve oxytetracycline forinjection or oral liquid administration. U.S. Pat. No. 5,071,643 to Yuet al., issued Dec. 10, 1991 and U. S. Pat. No. 5,360,615 also to Yu etal., issued Nov. 1, 1994, used polyethylene glycol and an acid or a baseto dissolve ibuprofen, naproxen, indomethacin or acetaminophen (amongothers).

[0011] Another solvent system, found in U.S. Pat. No. 5,505,961 toShelley et al., issued Apr. 9, 1996, used polyethylene glycol and sodiumor potassium acetate to enhance the solubility of acetaminophen.

[0012] Despite these efforts, there is still a strong need in the artfor solvent systems that can dissolve large amounts of a medicament,especially without the addition of large amounts of an acid or base.

SUMMARY OF THE INVENTION

[0013] It is an object of the present invention to provide a solventsystem capable of producing a highly concentrated solution of apharmaceutical agent suitable for encapsulation into a softgel ofsuitable size without neutralizing large amounts of the agent.

[0014] It is a further object of the present invention to create such asolvent system that can be safely consumed by human beings.

[0015] It is a further object of the present invention to use such asolvent system to create a highly concentrated solution of a medicament,like acetaminophen or naproxen, suitable for use as a fill in a softgel.About a one ml softgel should encapsulate about 325 mg of acetaminophenor about 220 mg of naproxen.

[0016] It is a further object of the present invention to create asolvent system for enhancing the solubility of medicaments, includingsuch over-the-counter medicaments as pain relievers and cold remedies.

[0017] It is an advantage of the invention that one of the ingredientsin the solvent system may itself be an antifungal agent, therebyincreasing the safety of the solvent system during storage and handling.

[0018] Additional objects and advantages of the invention will be setforth in part in the description that follows, and in part will beobvious from the description.

[0019] To achieve the foregoing objects and in accordance with thepurpose of the invention, as embodied and broadly described herein, theinvention provides a pharmaceutically acceptable solution comprising amedicament and a solvent system. The solvent system comprises a lowmolecular weight polymer and a salt of an organic acid containing atleast three carbon atoms.

[0020] To further achieve the foregoing objects and in accordance withthe purpose of the invention, as embodied and broadly described herein,the invention provides a method for dissolving a large amount of amedicament in a small amount of solvent. The solvent comprises a lowmolecular weight polymer and a salt of an organic acid containing atleast three carbon atoms.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] We will now describe the preferred embodiments of the invention.

[0022] The formulation of the invention comprises three types ofsystems: (a) a solvent system; (b) a solvent system and a medicament;and (c) a solvent system, at least one medicament dissolved in thesolvent system, and a softgel surrounding the medicament and solventsystem.

[0023] The solvent system of the invention comprises a low molecularweight polymeric material and a salt of an organic acid containing atleast three carbon atoms. The system may also contain additionalingredients as set out below.

[0024] One part of the solvent system of the invention is a lowmolecular weight polymeric material. As used herein, “a low molecularweight” polymer is any polymer that is liquid or semi-solid at aboutroom temperature and pressure when combined in a solvent system or anypolymer that can dissolve in a limited amount of water to form a solventsystem. The particular identity of the polymeric entity selected as thesolvent will guide one skilled in the art to the appropriate molecularweight for the polymer. Since the polymer will be ingested into thehuman body, it must be safe and nontoxic (at least when used in theamounts contemplated herein). While the polymer need not beorganoleptically pleasing, the polymer preferably does not cause anyadverse side reactions or other detrimental effect on humans uponingestion.

[0025] Linear or branched polymers, of course, generally do not have asingle molecular weight. Rather, each strand in a polymer sample willhave a different length and the “molecular weight” of a polymer samplewill be the average molecular weight of the strands.

[0026] Acceptable polymers that may be used in the invention includepolyalkylene glycols and polyvinyl pyrollidones and analogs thereof,including various copolymers, polymer blends and modified polymersthereof. The polymers of the invention may also include polymericmaterials that are not ordinarily thought of as polymers, such asglycerin and propylene glycol The preferred polymers of the inventionare polyols, such as glycerin, propylene glycol and polyalkyleneglycols. More preferred are polyethylene glycols and polypropyleneglycols. More preferably, the polyethylene glycols of the invention havea molecular weight of less than about 1500, since polyethylene glycol1500 is reported to be solid at room temperature. (Molecular weights ofabout 1500 or above are not excluded from the invention to the extentthat the polymer may be semi-solid, liquid or soluble in limited amountsof water.) Most preferably, the molecular weight of the polyethyleneoxide is from about 400 to about 600 daltons, and the most preferredembodiment of the invention uses polyethylene glycol having a molecularweight of about 600. The solvent may comprise mixtures of materials aswell. For example, a polyethylene glycol having a molecular weight ofabout 600 may be obtained by using PEG 600 or about a 50/50 mixture ofPEG 400 and PEG 800.

[0027] The polymeric material preferably comprises from about 10% byweight to about 70% by weight of the solution of the invention. Morepreferably, the polymeric material comprises from about 15% by weight toabout 65% by weight of the solution and even more preferably, thepolymeric material comprises from about 20% by weight to about 55% byweight of the solution. Most preferably, the polymeric materialcomprises from about 30% by weight to about 50% by weight of thesolution of the invention. When blends of the polymers are used as asolvent, it is preferable, but not critical, that one species of polymerpredominates. Thus, in one preferred embodiment of the invention, thesolvent system comprises from about 15% to about 65% by weightpolyethylene glycol 600 and from 0% to about 5% by weight of (and morepreferably from 0% to about 2% by weight) propylene glycol.

[0028] In addition to the polymeric material, the invention alsocomprises a salt of an organic acid containing at least three carbonatoms. The salt helps to ionize the medicament, especially where themedicament is capable of forming a zwitterion, without relying on strongacids or bases.

[0029] Preferred cations for the salt are monovalent and divalentcations that are nontoxic and acceptable for human consumption. Thesecations include, but are not limited to, sodium, potassium, and calciumions. Alkali cations are preferred, and sodium is the most preferredcation.

[0030] The anion of the salt is an organic acid anion containing atleast three carbon atoms. Acceptable acid anions include those capableof forming a nontoxic salt with any of the cations of the invention.Although the preferred acid anions are from saturated aliphatic acidshaving from three to six carbon atoms, other acids are not excluded fromthe scope of the invention. Aromatic acids, saturated acids having morethan six carbon atoms, and unsaturated acids having more than threecarbon atoms may be used, so long as the acid forms a nontoxic salt.More preferred acids include mono, di- and tri- carboxylic acids havingthree to six carbon atoms, including propionic acid, pyruvic acid,citric acid, and butanoic acid. Propionic acid is the most preferredbecause it has antifungal properties.

[0031] In a highly preferred embodiment of the invention, the salt is asodium propionate salt that is added to the solution of the invention asa salt/water solution. Preferred concentrations of the salt solution arefrom about 40% by weight to a saturated solution of the salt in water.

[0032] The pH of this propionate solution may be adjusted by theaddition of small amounts of propionic acid, usually no more than about1-2% by weight of the propionate solution. So, the numbers in theexamples may be slightly incorrect.

[0033] The salt may comprise from about 2% by weight to about 40% byweight of the solution of the invention. More preferably, the saltcomprises from about 4% to about 35% by weight of the solution of theinvention, and even more preferably, from about 4% by weight to about25% by weight of the solution of the invention. Preferably the pH isadjusted in the saltwater solution to provide acceptable pH limits inthe softgel.

[0034] The solvent system of the invention may also contain additionalingredients such as cosolvents, including dimethyl isosorbide, oils,including soybean oil, and water. The cosolvent may comprise from 0% byweight to about 30% by weight of the solution of the invention, and morepreferably from about 5% by weight to about 20% by weight of thesolution of the invention. Most preferably, the cosolvent is dimethylisosorbide and comprises from about 5% by weight to about 10% by weightof the solution of the invention. Water may comprise from 0% by weightto about 25% by weight of the solution of the invention. Oils maycomprise from 0% to about 20% by weight of the solution of theinvention, and more preferably from 0% to about 15% by weight of thesolution of the invention. In the examples that follow, water is addedas part of a sodium propionate solution that is added to the solventsystem. In some of these examples, the reported amounts in grams werecalculated from the density and volume of the propionate solution added.

[0035] The medicament of the invention may be any medicament, but thesoftgels of the invention are of primary benefit in human consumption,so the medicaments of the invention are preferably those intended foruse by humans. Preferred medicaments are those used in over-the-countertreatments of coughs, colds and other common ailments. Thus, highlypreferred medicaments include pain relievers, such as aspirin,acetaminophen, naproxen, ibuprofen and other nonsteroidalanti-inflammatory drugs, as well as the so-called “Cox-2” inhibitors.Other highly preferred medicaments include, but are not limited to,cough suppressants, such as dextromethorphan, decongestants, such aspseudoephedrine, and antihistamines, such as chlorpheniramine anddoxylamine compounds. Medicaments that form zwitterions when dissolvedwith the salts of the invention are most highly preferred.

[0036] The total amount of medicaments of the invention may comprisefrom about 25% by weight of the solution up to the amount that will forma fully saturated solution, usually up to about 70% by weight of thesolution. Preferably, however, the medicaments comprise from about 30%by weight to about 55% by weight of the solution of the invention. Ofcourse, dosage levels will be adjusted to reflect the needs of thepatient, not the needs of the solvent.

[0037] Consumer preference suggests that clear or at least translucentsolutions should be used in softgels. The solvent system of the presentinvention may be adjusted to provide such a clear solution acceptable toconsumers. In the examples that follow, many of the solutions have acolor. The color may be significantly reduced by carrying out thesolution process in the absence of oxygen. While the examples used anitrogen blanket, the solution was exposed to air while variousmaterials were added, which affected the final color of the solution.

[0038] The medicament should remain in solution to achieve the benefitsof the invention, and the solution should remain stable over time andunder conditions normally encountered in consumer applications. Thesolution disclosed in the present invention has been found stable androbust in a number of tests. For instance, the solution has been placed“on the shelf” at room temperature for extended periods of time, and hasremained clear and stable, without precipitation of the medicament.Moreover, the solution has been subjected to alternating refrigerationand room temperature conditions, and the medicament has notcrystallized, and has remained stable and clear.

[0039] The solution has been placed in softgels successfully, at leaston an experimental level. The gelatin in a softgel may be any known onthe art. Suitable results have been achieved with Type A gelatin, bloomstrength 150. Hydrophilic softgels are preferred.

[0040] The selection of ingredients to be used in the solvent systemwill, of course, depend on the medicament to be administered. Differentmedicaments, such as naproxen, aspirin and acetaminophen, have differentchemical structures and different affinities for various solventcombinations. Highly concentrated solutions of medicaments, such asaspirin and naproxen, require a solvent system tailored to the specificneeds of the medicament.

[0041] The solution of the invention may be prepared through mixing ofthe ingredients. This mixing takes place preferably at an elevatedtemperature and with applied shear. While the applied shear does notnecessarily allow for greater solubility of any ingredient, it appearsto provide better stability of the solution during handling and storage.Preferably, the solvent is prepared first and the medicament is thenadded to the solvent. The salt is then also added slowly to helpdissolve the medicament. It appears that if the salt is added tooquickly, ionization of the medicament does not take place and thematerial does not form a successful solution. The process may be carriedout in whole or in part in a nitrogen atmosphere if the presence ofoxygen might discolor or otherwise damage any ingredient in thesolution.

[0042] Preferred embodiments of the invention have been prepared asdescribed in the examples below. A solution of polyethylene glycol 600and, optionally, dimethyl isosorbide is prepared in a glass flask, andis stirred at about 250 rpm, and heated to about 50° C. (An acceptablesolution may be prepared without dimethyl isosorbide.) The flask maythen be deaerated with nitrogen. Acetaminophen or another medicament isadded and a stopper is used to cover the flask. Next, the sodiumpropionate solution is added dropwise, using a metered flow controldevice. The formulation is again blanketed with nitrogen and thenstirred at about 300 rpm with heat until clear, which usually requiresfrom about 30 to about 120 minutes. Another preferred embodimentincorporates shear to help the materials to blend more quickly andthoroughly.

EXAMPLES

[0043] The following examples are intended to demonstrate someembodiments of the invention without limiting the scope or spirit of theinvention. Due to rounding, total percentages for some of theformulations described below do not equal 100%. In some examples theamount of added propionate solution was recorded in mls. of solutionadded. This recorded number was converted to grams using an approximatedensity of 1.17 to 1.18

Example 1

[0044] A solution was prepared having the formulation set forth in Table1 as follows. The polyethylene glycol, dimethyl isosorbide and soybeanoil were combined in a 250 ml flask. This mixture was heated to about45° C. and stirred at about 250 rpm. The flask was blanketed withnitrogen gas, and acetaminophen was added as quickly as possible toreduce discoloration of the solution. A solution containing the waterand the sodium propionate was slowly added to the mixture. A clear,brown colored solution was obtained. Due to rounding, the percentages donot add up to 100%. TABLE 1 Formulation of Example 1 Ingredient AmountWeight Percent (%) Polyethylene glycol 600 25 g  25%  Dimethylisosorbide 15 g  15%  Water 5 g 5% Soybean oil 16 g  16%  Sodiumpropionate 5.5 g   5.5%   Acetaminophen 33 g  33%  Chlorpheniramine 0 g0% Pseudoephedrine 0 g 0% Dextromethorphan 0 g 0% Doxylamine succinate 0g 0% Propylene glycol 0 g 0%

Example 2

[0045] A formulation was prepared with the ingredients set forth inTable 2. The polyethylene glycol and dimethyl isosorbide were mixed, anda slurry of the sodium propionate and water was added to the mixture.This mixture was heated to 45° C. and stirred to dissolve the slurry.The acetaminophen was added in 5-gram portions, and complete solubilitywas obtained, providing a clear, light pink colored solution. Althoughsome crystallization was observed upon cooling, only minimalprecipitation had been observed after storage for ten days at roomtemperature. TABLE 2 Formulation of Example 2 Ingredient Amount WeightPercent (%) Polyethylene glycol 600 35 g  43%  Dimethyl isosorbide 5 g6% Water 4 g 5% Soybean oil 0 g 0% Sodium propionate 5 g 6%Acetaminophen 32.5 g   40%  Chlorpheniramine 0 g 0% Pseudoephedrine 0 g0% Dextromethorphan 0 g 0% Doxylamine succinate 0 g 0% Propylene glycol0 g 0%

Example 3

[0046] A formulation was prepared with the ingredients set forth inTable 3. Polyethylene glycol 600 and dimethyl isosorbide were combined,heated to 45° C., and stirred. The sodium propionate was mixed with thewater to form a solution and added to the solvents. Acetaminophen wasadded, and a clear, pink colored solution was obtained. TABLE 3Formulation of Example 3 Ingredient Amount Weight Percent (%)Polyethylene glycol 600 21 g  20%  Dimethyl isosorbide 6 g 6% Water 15g  14%  Soybean oil 0 g 0% Sodium propionate 12 g  11%  Acetaminophen 51g  49%  Chlorpheniramine 0 g 0% Pseudoephedrine 0 g 0% Dextromethorphan0 g 0% Doxylamine succinate 0 g 0% Propylene glycol 0 g 0%

Example 4

[0047] A formulation was prepared with the ingredients set forth inTable 4. A solution of the sodium propionate in the water was preparedby mixing at room temperature until dissolved. The polyethylene glycoland the dimethyl isosorbide were put into a 125-ml glass-stopperedErlenmeyer flask. The mixture was stirred and heated and blanketed withnitrogen. The acetaminophen was then added, and the sodium propionatesolution was then added. A clear, pink colored solution was obtained.After placing the solution in a freezer for four hours, the solution wasremoved and allowed to return to room temperature. No crystallizationwas observed. TABLE 4 Formulation of Example 4 Ingredient Amount WeightPercent (%) Polyethylene glycol 600 39.6 g   40%  Dimethyl isosorbide6.2 g   6% Water 10 g  10%  Soybean oil 0 g 0% Sodium propionate 7.9 g  8% Acetaminophen 33 g  34%  Chlorpheniramine 0 g 0% Pseudoephedrine 0 g0% Dextromethorphan 0 g 0% Doxylamine succinate 0 g 0% Propylene glycol1.8 g   2%

Example 5

[0048] A formulation was prepared with the ingredients set forth inTable 5. A sodium propionate solution was prepared by dissolving 40grams of sodium propionate in 50 mls of water. Polyethylene glycol anddimethyl isosorbide were then placed in a 250-ml distillation flask,stirred and heated. The acetaminophen was then added and nitrogen wasblown into the stopper of the flask to keep oxygen away from thesolution. 20-21 ml of the propionate solution were then added to theflask and stirring continued until a clear, pink colored solution wasobtained. This solution was blanketed with nitrogen, stoppered andfrozen for 16 hours. The solution then returned to room temperature, andslight crystal formation was observed on the surface of the solution.TABLE 5 Formulation of Example 5 Ingredient Amount Weight Percent (%)Polyethylene glycol 600 42.4 g   39%  Dimethyl isosorbide 9.94 g   9%Water 13.7 g   12%  Soybean oil 0 g 0% Sodium propionate 11 g  10% Acetaminophen 32.7 g   30%  Chlorpheniramine 0 g 0% Pseudoephedrine 0 g0% Dextromethorphan 0 g 0% Doxylamine succinate 0 g 0% Propylene glycol0 g 0%

Example 6

[0049] A formulation was prepared with the ingredients set forth inTable 6. A sodium propionate solution was prepared by dissolving 40grams of sodium propionate in 50 mls of water. Polyethylene glycol anddimethyl isosorbide were then placed in a 250-ml distillation flask,stirred and heated. The acetaminophen was then added and nitrogen wasblown into the stopper of the flask to keep oxygen away from thesolution. 20-21 ml of the propionate solution were then added to theflask and stirring continued until a clear, pink colored solution wasobtained. This solution was blanketed with nitrogen, stoppered andfrozen for 16 hours. The solution was then returned to room temperature,and slight crystal formation was observed on the bottom of the solution.TABLE 6 Formulation of Example 6 Ingredient Amount Weight Percent (%)Polyethylene glycol 600 29.5 g   27%  Dimethyl isosorbide 19.9 g   19% Water 13.7 g   13%  Soybean oil 0 g 0% Sodium propionate 11 g  10% Acetaminophen 33.2 g   31%  Chlorpheniramine 0 g 0% Pseudoephedrine 0 g0% Dextromethorphan 0 g 0% Doxylamine succinate 0 g 0% Propylene glycol0 g 0%

Example 7

[0050] A formulation was prepared with the ingredients set forth inTable 7. A sodium propionate solution was prepared by dissolving 40grams of sodium propionate in 50 mls of water. Polyethylene glycol anddimethyl isosorbide were then placed in a 250-ml distillation flask,stirred and heated. The acetaminophen was then added and nitrogen wasblown into the stopper of the flask to keep oxygen away from thesolution. 20-21 ml of the propionate solution were then added to theflask and stirring continued until a clear, pink colored solution wasobtained. This solution was blanketed with nitrogen, stoppered andfrozen for 16 hours. The solution was then allowed to return to roomtemperature, and no crystal formation was observed. TABLE 7 Formulationof Example 7 Ingredient Amount Weight Percent (%) Polyethylene glycol600 27.2 g   24%  Dimethyl isosorbide 28.8 g   25%  Water 13.7 g   12% Soybean oil 0 g 0% Sodium propionate 11 g  10%  Acetaminophen 33 g  29% Chlorpheniramine 0 g 0% Pseudoephedrine 0 g 0% Dextromethorphan 0 g 0%Doxylamine succinate 0 g 0% Propylene glycol 0 g 0%

Example 8

[0051] A formulation was prepared with the ingredients set forth inTable 8. The polyethylene glycol and the dimethyl isosorbide were placedinto a 250-ml distillation flask, heated to 50° C. and stirred. Thechlorpheniramine was added and stirring continued until it wascompletely dissolved. The acetaminophen was then added and the flask wasblanketed with nitrogen. 20 ml of a sodium propionate solution (600 gsodium propionate in 800 ml water) was added to the flask and thenitrogen blanket was reapplied. Stirring continued for about two hours.Pseudoephedrine was then added and stirring continued overnight. Acloudy, light yellow solution was obtained. An additional 5 ml of thesodium propionate solution was added, the solution was reheated andstirring continued until a clear, light orange colored solution wasobtained. TABLE 8 Formulation of Example 8 Ingredient Amount WeightPercent (%) Polyethylene glycol 600 38.2 g   34%  Dimethyl isosorbide12.9 g   11% Water 15.1 g   12%  Soybean oil 0 g 0% Sodium propionate10.5 g   9% Acetaminophen 37.6 g   31%  Chlorpheniramine 0.24 g   0.2%  Pseudoephedrine 3.2 g   2.8%   Dextromethorphan 0 g 0% Doxylaminesuccinate 0 g 0% Propylene glycol 0 g 0%

Example 9

[0052] A formulation was prepared with the ingredients set forth inTable 9. The polyethylene glycol was charged into a 250-ml distillationflask and heated to 50° C. and stirred. The acetaminophen was added tothe flask, and the flask was blanketed with nitrogen while stirring andheating continued. 30 mls of the sodium propionate solution were added,the nitrogen blanket was reapplied and stirring continued for two hoursuntil a light pink solution was obtained. After the solution was kept inthe freezer overnight and then placed in warm water some crystalsappeared, so an additional 5 ml of the sodium propionate solution wasadded under heat and stirring to redissolve the crystals. TABLE 9Formulation of Example 9 Ingredient Amount Weight Percent (%)Polyethylene glycol 600 50.1 g   40%  Dimethyl isosorbide 0 g 0% Water22.9 g   18%  Soybean oil 0 g 0% Sodium propionate 18.4 g   15% Acetaminophen 33.5 g   27%  Chlorpheniramine 0 g 0% Pseudoephedrine 0 g0% Dextromethorphan 0 g 0% Doxylamine succinate 0 g 0% Propylene glycol0 g 0%

Example 10

[0053] A formulation was prepared using the ingredients set forth inTable 10. The PEG-600 was added to a tared, 250-ml glass-stoppered flaskand blanketed with nitrogen. The PEG-600 was heated to about 60° C. withstirring. The acetaminophen was then added slowly and the mixture wasblanketed with nitrogen. Sodium propionate solution was prepared bydissolving 500 grams of sodium propionate into 500 mls water. Thissolution was then added dropwise to the flask until a clear, yellowcolored solution was obtained. The percentages do not add up to 100% dueto rounding errors. TABLE 10 Formulation of Example 10 Ingredient AmountWeight Percent (%) Polyethylene glycol 600 54.8 g 54%  Dimethylisosorbide 0 0% Water 7.1 g 7% Soybean oil 0 0% Sodium propionate 7.1 g7% Acetaminophen 33.4 g 33%  Chlorpheniramine 0 0% Pseudoephedrine 0 0%Dextromethorphan 0 0% Doxylamine succinate 0 0% Propylene glycol 0 0%

Example 11

[0054] A formulation was prepared with the ingredients set forth inTable 11. A flask was charged with PEG-600 and heated to about 55° C.The PEG was blanketed with nitrogen and stirred with an impeller bladeat about 200 rpm. Acetaminophen was slowly added over a 25-minute periodto form a fully wetted white slurry. A 1:1 by weight sodium propionatesolution (in water) was added to the mix dropwise at about 4 to 5 dropsper minute while the slurry was maintained under nitrogen and whilestirring continued at about 200 rpm. The temperature of the PEG wasmaintained at about 48° to about 55° C. A clear, pink colored solutionwas obtained. The pH of the sodium propionate solution was adjusted from9.1 to 7.1 by the addition of a small amount of undiluted propionicacid. The percentages do not add up to 100% due to rounding errors.TABLE 11 Formulation of Example 11 Ingredient Amount Weight Percent %Polyethylene glycol 600 262 g  51%  Dimethyl isosorbide 0 g 0% Water38.4 g 7.5%   Soybean oil 0% 0% Sodium propionate solution 38.4 g 7.5%  Acetaminophen 170.5 g  33%  Chlorpheniramine 0 g 0% Pseudoephedrine 0 g0% Dextromethorphan 0 g 0% Doxylamine succinate 0 g 0% Propylene glycol0 g 0%

Example 12

[0055] A formulation was prepared with the ingredients set forth inTable 12. The PEG-600 was added to 250-ml glass-stoppered distillationflask. A stir bar was added to the flask, and the PEG was heated toabout 60° C. with stirring. The pseudoephedrine was mixed with 1.5 mlwater and dissolved in the PEG. The acetaminophen was then added slowly,and the temperature was lowered to 50-55° C. The flask was blanketedwith nitrogen. A 1:1 by weight solution of sodium propionate in waterwas prepared. About 16 ml of the sodium propionate solution was addedslowly to the flask over two hours. A clear, pink/orange coloredsolution was obtained. An additional 5 ml of the sodium propionatesolution was added after 24 hours to redissolve some crystals that hadsettled out overnight. The pH of the sodium propionate solution had beenadjusted to 6.8 by the addition of undiluted propionic acid. Due torounding errors: the percentages do not add up to 100%/ TABLE 12Formulation of Example 12 Ingredient Amount Weight Percent %Polyethylene glycol 600 51 g 45% Dimethyl isosorbide  0 g  0% Water  0 g11% Soybean oil  0 g  0% Sodium propionate 12.4 g   11% Acetaminophen 35g 31% Chlorpheniramine  0 g  0% Pseudoephedrine  0 g  3%Dextromethorphan  0 g  0% Doxylamine succinate  0 g  0% Propylene glycol 0 g  0%

Example 13

[0056] A formulation was prepared with the ingredients set forth inTable 13. The PEG-600 was added to 250-ml glass-stoppered distillationflask. A stir bar was added to the flask, and the PEG was heated toabout 60° C. with stirring. The pseudoephedrine was mixed with 1.5 mlwater and dissolved in the PEG. The acetaminophen was then added slowly,and the temperature was lowered to 50-55° C. The flask was blanketedwith nitrogen. The 1:1 by weight sodium propionate solution was addedslowly over two hours. A clear, pink colored solution was obtained. ThepH of the sodium propionate solution was adjusted to 6.8 by the additionof undiluted propionic acid. The percentages do not add up to 100% dueto rounding errors. TABLE 13 Formulation of Example 13 Ingredient AmountWeight Percent (%) Polyethylene glycol 600 50 g  48% Dimethyl isosorbide0 g  0% Water 9.2 g    9% Soybean oil 0 g  0% Sodium propionate 7.7 g   7% Acetaminophen 34 g  33% Chlorpheniramine 0.25 g   0.2% Pseudoephedrine 0 g  3% Dextromethorphan 0 g  0% Doxylamine succinate 0g  0% Propylene glycol 0 g  0%

Example 14

[0057] A formulation was prepared with the ingredients set forth inTable 14. The PEG-600 was added to 250-ml glass-stoppered distillationflask. A stir bar was added to the flask, and the PEG was heated toabout 60° C. with stirring. The pseudoephedrine was mixed with 1.5 mlwater and dissolved in the PEG. The acetaminophen was then added slowly,and the temperature was lowered to 50-55° C. The flask was blanketedwith nitrogen. The 1:1 by weight sodium propionate solution was addedslowly over about one hour. A clear, pink colored solution was obtained.The pH of the sodium propionate solution was adjusted to 6.8 by theaddition of undiluted propionic acid. The percentages do not add up to100% due to rounding errors. TABLE 14 Formulation of Example 14Ingredient Amount Weight Percent (%) Polyethylene glycol 600   57 g42.9% Dimethyl isosorbide   0 g 0% Water 12.7 g 10.6% Soybean oil   0 g0% Sodium propionate solution 11.2 g  9.4% Acetaminophen   35 g 29.4%Chlorpheniramine   0 g 0% Pseudoephedrine   0 g  2.5% Dextromethorphan0.15 g  0.1% Doxylamine succinate   0 g 0% Propylene glycol   0 g 0%

Example 15

[0058] A formulation was prepared with the ingredients set forth inTable 15. The PEG-600 was added to 250-ml glass-stoppered distillationflask. A stir bar was added to the flask, and the PEG was heated toabout 60° C. with stirring. The pseudoephedrine was mixed with 1.5 mlwater and dissolved in the PEG. The acetaminophen was then added slowly,and the temperature was lowered to 50-55° C. The flask was blanketedwith nitrogen. The 1:1 by weight sodium propionate solution was addedslowly over two hours. A clear, pink colored solution was obtained. ThepH of the sodium propionate solution was adjusted to 6.8 by the additionof undiluted propionic acid. After 24 hours, some fine crystals appearedat the bottom of the flask. The percentages do not add up to 100% due torounding errors. TABLE 15 Formulation of Example 15 Ingredient AmountWeight Percent (%) Polyethylene glycol 600   51 g 42.8% Dimethylisosorbide   0 g 0% Water 15.1 g 12.7% Soybean oil   0 g 0% Sodiumpropionate 13.6 g 11.4% Acetaminophen   36 g 30.2% Chlorpheniramine 0.25g  0.2% Pseudoephedrine   3 g  2.5% Dextromethorphan 0.16 g  0.1%Doxylamine succinate   0 g 0% Propylene glycol   0 g 0%

Example 16

[0059] A formulation was prepared with the ingredients set forth inTable 16. The PEG-600 was added to 250-ml glass-stoppered distillationflask. A stir bar was added to the flask, and the PEG was heated toabout 60° C. with stirring. The pseudoephedrine was mixed with 1.5 mlwater and dissolved in the PEG. The acetaminophen was then added slowly,and the temperature was lowered to 50-55° C. The flask was blanketedwith nitrogen. 23 ml of a 1:1 by weight sodium propionate solution wasadded slowly over two hours. A clear, light orange colored solution wasobtained. The pH of the sodium propionate solution was adjusted to 6.8by the addition of undiluted propionic acid. After 24 hours, somecrystal had appeared on the bottom of the flask. The solution wereheated to 55° C. with stirring and an additional 4 ml of the sodiumpropionate solution were added. The percentages do not add up to 100%due to rounding errors. TABLE 16 Formulation of Example 16 IngredientAmount Weight Percent % Polyethylene glycol 600   50 g 40.6% Dimethylisosorbide   0 g 0% Water 017.4 g  14.1% Soybean oil   0 g 0% Sodiumpropionate 15.9 g 12.9% Acetaminophen   36 g 29.2% Chlorpheniramine   0g 0% Pseudoephedrine   0 g  2.4% Dextromethorphan 0.16 g  0.1%Doxylamine succinate 0.72 g  0.6% Propylene glycol   0 g 0%

Example 17

[0060] A formulation was prepared with the ingredients set forth inTable 17. The ingredients were mixed and the sample was heated in asteam bath and swirled until dissolved. The potassium hydroxide wasadded as a solution of 6.8 g KOH in 100 mls of water. The sodiumpropionate was added as a solution of 500g sodium propionate in 700 mlsof water. A clear solution was obtained. TABLE 17 Formulation of Example17 Weight Percent Ingredient Amount (%) Naproxen sodium 3.0033 g 21.67Polyethylene Glycol 300 10.0332 g 72.40 Potassium hydroxide 6.66 mg 0.05Sodium propionate 0.8153 g 5.88

[0061] In each of the above examples, the solutions obtained werestable, and the acetaminophen did not precipitate. Also, in each of theabove examples, we observed no evidence of acetaminophen degradation.Assay values showed greater than 98% recovery after ten weeks stored atroom temperature under nitrogen.

[0062] Several of the solutions of the examples have been successfullyincorporated into soft gelatin capsules using techniques well known inthe art.

[0063] The purpose of the above description is to illustrate someembodiments of the invention without implying a limitation. It will beapparent to those skilled in the art that various modifications andvariations may be made in the apparatus or procedure of the inventionwithout departing from the scope or spirit of the invention.

We claim:
 1. A pharmaceutically acceptable solution comprising amedicament and a solvent system, wherein said solvent system comprises alow molecular weight polymeric material and a salt of an organic acidcontaining at least three carbon atoms.
 2. The solution of claim 1,wherein said medicament is capable of forming a zwitterion.
 3. Thesolution of claim 2, wherein said medicament is acetaminophen.
 4. Thesolution of claim 1, wherein said medicament comprises at least about25% by weight of said solution.
 5. The solution of claim 1, wherein saidpolymeric material is selected from the group consisting of polymers ofalkylene glycols, copolymers thereof, polymers of vinyl pyrollidones,copolymers thereof, glycerin, propylene glycol and mixtures and analogsthereof.
 6. The solution of claim 1, wherein said polymeric material isselected from the group consisting of polymers and copolymers ofethylene glycol.
 7. The solution of claim 6, wherein said polymericmaterial has an average molecular weight of less than about 1,500daltons.
 8. The solution of claim 1, wherein said polymeric materialcomprises from about 10% to about 70% by weight of the solution.
 9. Thesolution of claim 1, wherein said salt is an alkali propionate.
 10. Thesolution of claim 1, wherein said salt comprises from about 2% by weightto about 40% by weight of the solution.
 11. The solution of claim 1,further comprising a cosolvent.
 12. A gelcap for administering amedicament comprising an outer shell comprising gelatin fully orpartially enclosing a solution comprising a medicament and a solventsystem, wherein said solvent system comprises a low molecular weightpolymeric material and a salt of an organic acid containing at leastthree carbon atoms.
 13. The gelcap of claim 12, wherein said medicamentis an analgesic.
 14. The gelcap of claim 13, wherein said medicament isacetaminophen.
 15. The gelcap of claim 12, wherein said medicamentcomprises at least about 25% by weight of said solution.
 16. The gelcapof claim 12, wherein said polymeric material is selected from the groupconsisting of polymers of alkylene glycols, copolymers thereof, polymersof vinyl pyrollidones, copolymers thereof, glycerin, propylene glycoland mixtures and analogs thereof.
 17. The gelcap of claim 12, whereinsaid polymeric material is selected from the group consisting ofpolymers and copolymers of ethylene glycol.
 18. The gelcap of claim 17,wherein said polymeric material has a molecular weight of less thanabout 1,500 daltons.
 19. The gelcap of claim 12, wherein said polymericmaterial comprises from about 10% to about 70% by weight of thesolution.
 20. The gelcap of claim 12, wherein said salt is an alkalipropionate.
 21. The gelcap of claim 12, wherein said salt comprises fromabout 2% by weight to about 40% by weight of the solution.
 22. Thegelcap of claim 12, further comprising a cosolvent.
 23. A method ofmaking a solution comprising the steps of: (a) preparing a solventcomprising a low molecular weight polymeric material; (b) adding amedicament to said solvent system to form a solution; and (c) blending asalt of an organic acid containing at least three carbon atoms with saidpolymeric material to form a solvent system.
 24. The method of claim 23,further comprising the step of heating at least one of said solvent,said solvent system or said solution.